Unknown

Dataset Information

0

Tislelizumab uniquely binds to the CC' loop of PD-1 with slow-dissociated rate and complete PD-L1 blockage.


ABSTRACT: Programmed cell death protein 1 (PD-1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well-known target for cancer immunotherapy. Tislelizumab (BGB-A317) is an anti-PD-1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM-CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of tislelizumab, and demonstrated that the CC' loop of PD-1, a region considered to be essential for binding to PD-1 ligand 1 (PD-L1) but not reported as targeted by other therapeutic antibodies, significantly contributes to the binding of tislelizumab. The binding surface of tislelizumab on PD-1 overlaps largely with that of the PD-L1. SPR analysis revealed the extremely slow dissociation rate of tislelizumab from PD-1. Both structural and functional analyses align with the observed ability of tislelizumab to completely block PD-1/PD-L1 interaction, broadening our understanding of the mechanism of action of anti-PD-1 antibodies.

SUBMITTER: Hong Y 

PROVIDER: S-EPMC7931243 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Tislelizumab uniquely binds to the CC' loop of PD-1 with slow-dissociated rate and complete PD-L1 blockage.

Hong Yuan Y   Feng Yingcai Y   Sun Hanzi H   Zhang Bo B   Wu Hongfu H   Zhu Qing Q   Li Yucheng Y   Zhang Tong T   Zhang Yilu Y   Cui Xinxin X   Li Zhuo Z   Song Xiaomin X   Li Kang K   Liu Mike M   Liu Ye Y  

FEBS open bio 20210216 3


Programmed cell death protein 1 (PD-1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well-known target for cancer immunotherapy. Tislelizumab (BGB-A317) is an anti-PD-1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM-CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of  ...[more]

Similar Datasets

| S-EPMC6418176 | biostudies-literature
| S-EPMC7792774 | biostudies-literature
| S-EPMC7378575 | biostudies-literature
| S-EPMC6917757 | biostudies-literature
| S-EPMC5353958 | biostudies-other
| S-EPMC10141313 | biostudies-literature
| S-EPMC9279048 | biostudies-literature
| S-EPMC11476265 | biostudies-literature
| S-EPMC5784856 | biostudies-other
| S-EPMC7394266 | biostudies-literature